SK4442000A3 - Process and intermediates for preparing anti-cancer compounds - Google Patents

Abstract

The present invention relates to methods and intermediates for preparing compounds of the formula 1    and the pharmaceutically acceptable salts and solvates thereof, as well as structurally related compounds, wherein R¹, R² and R¹⁵ are as defined herein. The foregoing compounds are useful in the treatment of hyperproliferative disorders, such as cancers, in mammals.

The present invention also relates to a method of preparing compounds of the formula 9    and the pharmaceutically acceptable salts and solvates thereof, wherein R⁶-R¹⁰ and R¹⁵ are as defined herein.

Description

Process for the preparation of anticancer compounds and intermediates of this process

Technical field

The invention relates to a process for the preparation of compounds which can be used in the treatment of hyperproliferative diseases, for example cancer, in mammals.

BACKGROUND OF THE INVENTION

U.S. Patent 5,747,498, issued May 5, 1998 and incorporated herein by reference, relates to a new series of quinazoline derivatives including [6,7-bis (2-methoxyethoxy) quinazolin-4-yl] (3-ethynylphenyl) amine hydrochloride, which are inhibitors of the erbB family of oncogenic and proto-oncogenic protein tyrosine kinases, for example epidermal growth factor receptor (EGFR), and which can thus be used in the treatment of proliferative diseases, for example cancer in humans. US patent application entitled N- (3-ethynylphenylamino) -6,7-bis (2-methoxyethoxy) -4quinazolin-amine Mesylate Anhydrate And Monohydrate, filed April 29, 1998, in which T. Norris, D. Santafianos are designated as inventors. , DJM Alien, R.M. Shanker and J.W.

Raggon (Attorney docket PC 10074), which is incorporated herein by reference, refers to N- (3-ethynyl-phenylamino) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine mesylate in anhydrous form and in the form of a hydrate having the same useful in the treatment of cancer as the above hydrochloride salt. The invention relates to processes for the preparation of the anticancer compounds disclosed in the aforementioned US patent and US patent application and intermediates of the process.

SUMMARY OF THE INVENTION

The invention relates to a process for the preparation of compounds of the formula I

and pharmaceutically acceptable salts and solvates of these compounds, wherein:

R ¹ and R ² are each independently selected from C 1 -C 10 alkyl and C 1 -C 10 alkoxy, wherein both alkyl and alkoxy are optionally substituted with a maximum of 2 substituents independently selected from hydroxy and C 1-6 alkoxy carbon atoms;

R ¹⁵ is hydrogen, C 1 -C 10 alkyl, or - (CH ₂ ) q (C 8 -C ₁₀ aryl) wherein q is an integer from 0 to 4;

which comprises treating a compound of formula 2

Wherein R, R ^A and R ² are as defined above and G represents a blocking group selected from -C (OH) R ³ R ⁴ and -SiR ³ R ⁴ R ⁵ ;

R ³ , R ⁴ and R ⁵ are each independently C 1 -C 6 alkyl;

either (a) an alkali metal or alkali metal hydroxide in a solvent containing a C 1 -C 10 alkyl group substituted with a hydroxy group when G is -C (OH, R ³ R ⁴⁾ , or (b) a tetra (C 1 -C 6 alkyl) ammonium fluoride compound in an aprotic solvent when G is -SiR ³ R ⁴ R ⁵ .

In a preferred embodiment wherein G is -C (OH) R ³ R ⁴ , the solvent is a secondary alcohol such as 2-butanol or isopropanol and the alkali metal or alkali metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, hydroxide magnesium and potassium hydroxide, with sodium hydroxide being most preferred.

In another preferred embodiment, where G is -SiR ^J R R, a-L-tetraíC CgalkyUamóniumfluoridovou compound of tetra (n-butyl) ammonium fluoride and the aprotic solvent is selected from tetrahydrofuran, diethyl ether, dimethoxyethane, toluene, dichloromethane, chloroform, and mixtures of two or a plurality of these solvents, with tetrahydrofuran being most preferred.

The invention also relates to the preparation of a compound of formula 2 as defined above, the method comprising treating a compound of formula 3.

wherein R ¹ and R 6 are as defined above, with a compound of formula 4

wherein G and R ^{1 have the} meanings defined for the compound of Formula 2.

In a preferred embodiment of the above method, the compound of formula 3 is treated with a compound of formula 4 in an organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile or a mixture of two or more of these solvents, more preferably acetonitrile.

The invention also relates to a process for the preparation of a compound of formula 3 as defined above, which process comprises treating a compound of formula 5

thionyl chloride in anhydrous dichloromethane.

In preferred embodiments of each of the reactions described above, R 1 and R 2 are both 2-methoxyethoxy and R ¹ is hydrogen.

The invention also relates to a process for the preparation of compounds of formulas 6 and 7

and the pharmaceutically acceptable salts and solvates thereof, wherein R ¹⁵ is as defined above, R ⁶ represents an alkyl group having 1 to 10 carbon atoms, or - (CH 2) _m O (CH 2) _n CH ₃ ;

R ⁷ represents an alkyl group having 1 to 10 carbon atoms or an alkylaryl group having 1 to 6 carbon atoms in the alkyl radical and 6 to 10 carbon atoms in the aryl radical, both of which are optionally substituted with 1 to 3 substituents independently selected from halo, nitro trifluoromethyl, trifluoromethoxy, alkylsulfonyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryloxy of 6 to 10 carbon atoms and arylsulfonyl of 6 to 10 carbon atoms;

each m is independently an integer from 1 to 6 and n is an integer from 0 to 3;

the method comprising treating a compound of Formula 8

wherein G ¹ is -C (OH) R ³ R ⁴ and R ¹⁵ , R ⁶ , R ³ and R ⁴ are as defined above, with a primary or secondary alcohol R ⁷ -OH, wherein R ^{7 is} as defined above, in in the presence of an alkali metal or an alkali metal hydroxide such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, with sodium hydroxide being most preferred.

In the most preferred embodiment of the above reaction, R ^{6 is} 2-methoxyethoxy and the alcohol of formula R ⁷ -OH is preferably a secondary alcohol.

The invention also relates to processes for the preparation of compounds of formula 9

and pharmaceutically acceptable salts and solvates thereof, wherein R ¹⁵ , R ⁶ and R ^{7 are} as defined above;

Q Q 1 Λ

R, R and R are each independently selected from hydrogen, C 1 -C 10 alkyl, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,

-OR ¹¹ , -C (O) R ¹³ ·, -C ¹² O ¹¹ , -NR ¹² C (O) OR ¹⁴ , -OC ¹² O ¹¹ , NR ¹² SO ² R ¹⁴ , -SO ² NR ¹¹ R ¹² , -NR ¹² C (O) R ¹³ -, -C (O) NR ^{1: L} R ¹² , -NR ^{13 1} * ¹² , -S (O) j (CH ₂ ) g (C ₆ -C ₁₀ aryl), -S (O) j (C (C 1 -C 6 alkyl) wherein j is an integer from 0 to 2, - (CH ₂ ) _q (C 8 -C ₁₀ aryl),

-O (CH ₂ ) _q (C ₆ -C ₁₀ aryl), -NR ¹² (CH ₂ ) _q (C ₈ -C ₁₀ aryl), and - (CH 2) q (4-10 membered heterockylus), wherein q is an integer from 0 to 4; said alkyl group optionally having 1 or 2 hetero groups selected from oxygen, -S (O) j - in which j is an integer from 0 to 2, and -N (R ¹² ) - provided that two oxygen atoms, two the sulfur atoms or the oxygen atom and the sulfur atom are not directly attached thereto; the aryl and heterockyl groups are optionally fused to an aryl group having 6 to 10 carbon atoms, a saturated cyclic group having 5 to 8 carbon atoms, or a 4- to 10-membered heterocyclic group; and the alkyl, aryl and heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR ¹² SO ₂ R ¹⁴ , -SO ₂ NR ^{1: L} R ¹² , -C (OR ¹¹ , -C (O) OR ¹³ ·),

-OC (O) R ¹³ -, -NR ¹² (O) R ¹¹ , -C (O) NR ¹¹ R ¹² , -NR ^{11 :} R ¹² , -OR ¹¹ , alkyl of 1 to 10 carbon atoms, - (CH ₂ ) _q (C 8 -C ₁₀ aryl) and - (CH ₂ ) _q (4- to 10-membered heterocycle) wherein q is an integer from 0 to 4;

each R ¹¹ is independently selected from hydrogen, C 1 -C 10 alkyl, - (CH ₂ ) _q (C 8 -C ₁₀ aryl), and - (CH ₂ ) _q (4- to 10-membered heterocycle); wherein q is an integer from 0 to 4; wherein the alkyl group optionally comprises 1 or 2 hetero groups selected from oxygen, -S (O) j - in which j is an integer from 0 to 2, and -N (R ^X ) - provided that two oxygen atoms, two the sulfur atoms or the nitrogen atom and the sulfur atom are not directly bound to each other; the aryl and heterocyclic groups R ¹¹ are optionally fused to an aryl group having 6 to 10 carbon atoms, a saturated cyclic group having 5 to 8 carbon atoms, or a 4- to 10-membered heterocyclic group; and the above R ¹¹ substituents, with the exception of hydrogen, are optionally substituted with 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R ¹² , -C (O) OR ¹² , -OC (O) R ¹² , -NR ¹² C (O) R ¹³ , -C (O) NR ¹² R ¹³ , -NR ¹² R ¹³ , hydroxy, C 1 -C 6 alkyl and alkoxy 1 to 6 carbon atoms;

R ^3-2 and R ³³ are each independently hydrogen or C 1 -C 6 alkyl; and

R ¹⁴ is selected from the substituents provided in the definition of R ¹¹ , except that R ^{14 is} not hydrogen;

the method comprising treating a compound of formula 10

wherein R ¹⁵ , R ⁶ , R ⁸ , R ⁹ and R ^{10 are} as defined above; a primary or secondary alcohol of the formula R -OH, in which R is as defined above, preferably a primary alcohol, in the presence of an alkali metal or alkali metal hydroxide such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and hydroxide potassium hydroxide, with sodium hydroxide being most preferred.

The above compounds of formulas 1, 6, 7 and 9 are useful in the treatment of hyperproliferative diseases, for example cancer, in mammals.

The invention also relates to the intermediates of formula (2) described above in connection with the preparation of the compounds of formula (1).

The term halo, as used herein, unless otherwise indicated, refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro, chloro and thio.

The term alkyl, as used herein, unless otherwise indicated, denotes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic moieties or combinations thereof. It will be appreciated that for an alkyl group to include cyclic moieties, it is desirable to contain at least 3 carbon atoms.

The term aryl, as used herein, unless otherwise indicated, refers to an organic radical derived from an aromatic hydrocarbon by removal of a single hydrogen atom, such as a phenyl or naphthyl radical.

The term 4- to 10-membered heterocycle, as used herein, unless otherwise indicated, denotes aromatic and non-aromatic heterocyclic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen, each of which has a heterocyclic group having in its heterocyclic system of 4 to 10 atoms. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include fused ring systems with benzene rings and ring systems substituted with one or more oxo groups. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is a thiazolyl group and an example of a 10-membered heterocyclic group is a quinolinyl group. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuran, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxazepinyl, diazepinyl, hiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxalanyl, pyrazolinyl, ditionyl, ditiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1. O] hexanyl, 3-azabicyclo [4.1.0] heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, chinothiazol, , isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridolyl, oxadiazolyl, puradinyl, puradinyl, purinyl benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl buy it. These groups may, where possible, be bonded via carbon or nitrogen. For example, the pyrrole-derived compound may be a 1-pyrrolyl group (nitrogen-linked) or a 3-pyrrolyl group (carbon-linked).

The term pharmaceutically acceptable salt (s) as used herein means, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of the invention. The compounds of the present invention which are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of these basic compounds are non-toxic acid addition salt forming compounds, i. salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, acid tartrate, ascorbate, succinate, succinate, succinate gentisinate, fumarate, gluconate, glucuronate, glucarate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate; 1,1'-methylene-bis- (2-hydroxy-3-naphthoate) salt. Compounds prepared according to the invention that include a basic moiety, for example an amino group, may form pharmaceutically acceptable salts in addition to the above listing of acids with different amino acids.

The compounds prepared by the process of the invention, which are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts, and in particular the calcium, magnesium, sodium and potassium salts of the compounds of the invention.

The compounds prepared by the process of the invention have asymmetric centers and therefore exist in various enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and stereoisomers of the compounds prepared according to the invention and mixtures thereof. The compounds of formula I may also exist as tautomers. The present invention relates to the use of all of these tautomers and mixtures thereof.

The invention also encompasses isotopically-labeled compounds prepared by the process of the invention and their pharmaceutically acceptable salts, which are identical to those already cited in relation to formula 1, but taking into account the fact that one or more atoms are replaced by an atom, which has an atomic mass or mass number different from the atomic mass or mass number, which is generally in its natural form. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ 0, ³⁵ S, ¹⁸ F, and ³⁶ C1. Compounds prepared by the process of the invention, prodrugs thereof, and pharmaceutically acceptable salts of these compounds or of said prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically-labeled compounds of the invention, for example, compounds in which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug testing and / or tissue substrate distribution. Tritium, ie.

³ H, and the ¹⁴ C carbon isotope are particularly preferred for their ease of preparation and detectability. In addition, substitution with heavier isotopes, for example deuterium, i. ² H, may offer certain therapeutic advantages resulting from higher metabolic stability, for example, an increase in the half-life in vivo, or a reduction in dosage requirements, which may be advantageous in certain circumstances. Isotopically-labeled compounds of the formula I according to the invention and their precursors can generally be prepared according to the procedures described in the reaction schemes and / or the exemplary section of the invention, replacing the non-isotopically-labeled reagent with a readily available isotopically-labeled reagent.

Reaction scheme 1

Reaction scheme 2

Reaction scheme 3

The methods of the invention illustrate Reaction Schemes 1 to 3. All reactions mentioned in these Reaction Schemes and described below, unless other conditions are specified, are carried out at atmospheric pressure and at room temperature (about 20-25 ° C). Also, substituents R ¹ to R ¹⁰ , R ¹⁵ , G and G ¹ , unless otherwise stated, have the meanings defined above.

According to Reaction Scheme 1, compounds of Formula 1 can be prepared by treating the starting compound of Formula 5, which can be prepared by methods known to those skilled in the art, thionyl chloride in anhydrous dichloromethane, at reflux temperature (about 38-42 ° C at atmospheric pressure). to give a compound of formula 3. A compound of formula 2 can be obtained by treating a compound of formula 3 with a compound of formula 4 in an organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile or a mixture of two or more of these solvents, preferably acetonitrile. which ranges from 50 ° C to reflux temperature and preferably at reflux temperature. The compound of formula 1 can then be prepared by treating a compound of formula 2 with an alkali metal or alkali metal hydroxide in a solvent containing a C 1 -C 10 alkyl group substituted with at least one hydroxy group when G is -C (OH) R ³ R ⁴ , or a tetraalkylammonium fluoride compound having 1 to 6 carbon atoms in the alkyl radicals in the presence of an aprotic solvent when G is -SiR ³ R ⁴ R ⁵ . When G is -C (OH) R ³ R ⁴ , the solvent is preferably a secondary alcohol, for example

The 2-butanol or isopropanol and the alkali metal or alkali metal hydroxide are selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, preferably sodium hydroxide and the reaction is carried out at a temperature of about

100 ° C to 150 ° C. When G is -SiR ³ R ⁴ R ⁵ , the tetraalkylammonium fluoride compound having 1 to 6 carbon atoms in the alkyl radicals is preferably tetra (n-butyl ammonium fluoride), the aprotic solvent being selected from tetrahydrofuran, diethyl ether, dimethoxymethane, toluene, dichloromethane and chloroform. two or more of these solvents, the preferred solvent being tetrahydrofuran and the reaction is preferably carried out at a temperature ranging from room temperature to about 70 ° C. The anti-cancer compounds of formula 1 can be converted into pharmaceutically acceptable salts as described below.

According to Reaction Scheme 2, anticancer compounds of formulas 6 and 7 can be prepared by treating intermediate 8 with a primary or secondary alcohol of formula R ⁷ -OH, wherein R ⁷ is as defined above, in the presence of an alkali metal or alkali metal hydroxide such as hydroxide sodium, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, preferably in the presence of sodium hydroxide at a temperature of about 100 ° C to 150 ° C. The use of a secondary alcohol of formula R ⁷ -0H will minimize conversion to the asymmetric analogue of formula 7, while use of a primary alcohol of formula R ⁷ -OH will increase the relative concentration of the asymmetric analogue of formula 7, depending on the analogue that is preferred, it may be a secondary or primary alcohol. The compounds of formulas 6 and 7 can be separated by a variety of methods well known to those skilled in the art, for example, by chromatography. The compounds of formulas 6 and 7 can be converted into pharmaceutically acceptable salts as described below.

According to Reaction Scheme 3, compounds of Formula 9 can be prepared by treating compounds of Formula 10 with a primary or secondary alcohol of formula R ⁷ -OH as described in Reaction Scheme 2. Because the reaction described in Reaction Scheme 3 aims to prepare an asymmetric analog, of an alcohol of formula R ⁷ -OH. The compounds of formula 9 can be converted readily into pharmaceutically acceptable salts as described above.

Some of the compounds described above prepared by the process of the invention may have asymmetric carbon atoms. Compounds having a mixture of isomers at one or more centers will exist as diastereomeric mixtures from which the individual diastereomers can be isolated due to their physicochemical differences by methods known to those skilled in the art, for example by chromatography or fractional crystallization. All such isomers, including mixtures of diastereomers, are within the scope of the invention.

The above-mentioned compounds, which are basic in nature, are capable of forming a variety of different salts with various inorganic and organic acids. Although these salts must be pharmaceutically acceptable for administration to mammals, in practice it is often desirable to first isolate a compound of the invention in the form of a pharmaceutically unacceptable salt from the reaction mixture and simply convert it back to the free base form with an alkaline reagent and subsequently convert it to a pharmaceutically acceptable an acid addition salt. The acid addition salts of the basic compounds of the invention are readily prepared by treating the basic compound with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent or in a suitable organic solvent, for example methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt may also be precipitated from a solution of the free base in an organic solvent by adding a solution of a suitable mineral or organic acid.

The above compounds, which are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and especially sodium and potassium salts. All of these salts are prepared by conventional techniques. The chemical bases which can be used as reagents for the preparation of the pharmaceutically acceptable base salts of the invention are those which form non-toxic base salts with the acidic compounds of the invention. Such non-toxic basic salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium, and the like. These salts can be readily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired alkali metal alkoxide or metal hydroxide and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, these salts can be prepared by mixing lower alkanol solutions of the acidic compounds with the desired alkali metal or metal hydroxide alkoxide and then evaporating the resulting solution to dryness. In both cases, stoichiometric amounts of reagents are preferably used to ensure complete reaction and maximum yields of the desired final product.

The following examples are illustrative only and are not to be construed as limiting the scope of the invention as set forth in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 3 - [(trimethylsilyl) ethynyl] nitrobenzene

A mixture of 1-bromo-3-nitrobenzene (10.0 g, 49.45 mmol) and trimethylsilylacetylene (8.4 mL, 59.34 mmol) was treated with triethylamine (33 mL) to give a small amount of white precipitate. The resulting mixture was treated with dichlorobis (triphenylphosphone) palladium II (7 mg, 0.01 mmol) and copper (I) iodide (8.5 mg, 0.04 mmol), heated to 80-85 ° C (oil bath temperature) and at this temperature. was maintained for 4 hours. The resulting bright yellow mixture was allowed to cool to room temperature and the solid was removed by filtration with triethylamine (33 mL). The clear, yellow solution was concentrated by evaporation and dried in vacuo overnight at room temperature to give the title product (11.11 g, 102% yield) as a dark brown oil. Gas chromatography / mass spectroscopy indicated that the final compound was 100% pure m / e 219 (M + H) ⁺ .

Example 2

Preparation of 3 - [(trimethylsilyl) ethynyl] aniline

A mixture of the nitro compound prepared as described above

3 - [(trimethylsilyl, ethynyl) nitrobenzene (0.86 g, 3.92 mmol, in 2-propanol (30 mL) was degassed with nitrogen and treated with 5% platinum on alumina (268 mg). The mixture was shaken under hydrogen for 22 h. The reaction mixture was filtered through a pad of Celite (diatomaceous earth) and concentrated by evaporation to give an oil which was dried overnight in vacuo to give the product (692 mg, 93 yield) as a solid. yellow-brown oil.

δ _Η (300 MHz, CDCl ₃ ) 0.24 (9H, s), 3.56 (2H, bs), 6.62 (1H, ddd, J = 1.0, 2.3 & 8.0), 6.78 (1H, t, J = 7.8); 6.87 (1H, t, J = 7.8); 6.87 (1H, dt, J = 7 and 1.2); Sq & a —45V (75.5

MHz? CDC1 ₃₎ 93.4, 105.4, 115.6, 118.2, 122.4, 123.8, 129.2, 146.2; m / e 190 (M + H) < ^{+ &gt};.

Example 3

Preparation of 6,7-bis (2-methoxyethoxy) -N- [3 [(trimethylsilyl) ethynyl] phenyl] -4-quinazolinamine monohydrochloride

4-Chloro-6,7-bis (2-methoxyethoxy) quinazoline (942 mg, 3.01 mmol) was treated with a solution of aniline (645 mg, 3.41 mmol) in 2-propanol (14 mL) and boiled under reflux for 2.5 hours. reflux condenser. The mixture was allowed to cool to room temperature and stirred for 1 hour. The solid was collected by filtration, rinsed with 2-propanol (5 mL) and dried in vacuo overnight to give the title product (1.33 g, 88% yield) as a white solid.

Δ _H (400 MHz; CDCl ₃ ) 0.21 (9H, s), 3.38 (3H, s), 3.41 (3H, s), 3.72 (2H, m), 3.77 (2H m), 4.10 (2H, s), 4.53 (2H, s) 7.20 (1H, t, J = 7.8); 7.23-7.28 (2H, m), 7.75 (1H, d, J = 7.8),

7.88 (1H, s), 8.20 (1H, s), 8.42 (1H, s); m / e 466 (M + H) < ^{+ &gt};.

Example 4

Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine monohydrochloride

6,7-Bis (2-methoxyethoxy) -N- [3 [(trimethylsilyl) ethynyl] phenyl] -4-quinazolinamine monohydrochloride suspension (1.22 g,

2.43 mmol) in tetrahydrofuran (6.1 mL) was treated with 1M flow of tetra-n-butylammonium fluoride in tetrahydrofuran (2.6 mL, 2.55 mmol) and stirred for 1 hour at room temperature. The solution was treated with 2-propanol (12.2 mL) and concentrated by evaporation. The oil in 2-propanol (20 mL) was treated with concentrated hydrochloric acid (0.2 mL) to give a precipitate. The mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, rinsed with 2-propanol (2 mL) and dried in vacuo to give the title product (747 mg, 72% yield) as an off-white solid (mp 226-229 ° C).

δ _Η (300 MHz; dg-DMSO) 3.36 (6H, s), 3.77-3.80 (4H, m) 4.30 (1H, S), 7.39 (1H, S), 7 41 (1H, d, J = 7.8), 7.50 (1H, t,

J = 7.9, 7.79 (1H, d, J = 8.1), 7.88 (1H, s), 8.40 (1H, s), 8.86 (1H, s) 11.48 (1 H, bs); Δ _C (100 MHz; dg-DMSO) 58.4, 58.5, 68.7, 69.2, 69.7, 67.0, 81.3, 83.0, 100.3, 105.2, 107.2, 121.9, 125.4, 127.6, 128.9, 129.2, 135.2, 137.7, 148.3, 149.2, 155.4, 158.0; m / e 394 (M + H) < ^{+ &gt};.

Example 5

Preparation of 4- [3 - [[6,7-bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] -2-methyl-3-butin-2-ol monohydrochloride

4-Chloro-6,7-bis (2-methoxyethoxy) quinazoline (15 g, 48 mmol), 4- (3-aminophenyl) -2-methyl-3-butin-2-ol (9.2 g, 52, 8 mmol) and acetonitrile (225 mL) were refluxed for 5 hours. The mixture was cooled to 5-10 ° C and stirred for one hour. The solid was collected by filtration, rinsed with acetonitrile (15 mL) and dried in vacuo overnight to give the title product (23.4 g, 100% yield) as a white solid.

δ _Η (400 MHz; dg-DMSO) 1.44 (6H, s), 3.31-3.32 (6H, m), 3.693.75 (4H, m), 4.24-4.30 (2H , m), 4.35-4.37 (2H, m), 7.25 (1H,

m), 7.39 (2H, m), 7.72-7.74 (2H, m), 8.47 (1H, s), 8.79 (1H, s), 11.64 (1H, s) )? m / e 452 (M + H) < ^{+ &gt};.

Example 6

Preparation of 4- [3 - [[6,7-bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] -2-methyl-3-butin-2-ol

4- [3 - [[6,7-Bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] 2-methyl-3-butin-2-ol monohydrochloride prepared as described above (19.0 g, 39, 7 mmol), water (95 mL) and ethyl acetate (380 mL) were stirred together at room temperature to give a mixture. The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide and the mixture was divided into two layers. After separation from the aqueous layer, the organic layer was concentrated under vacuum to a final volume of approximately 190 mL. After an ice bath granulation period, crystals of the title product formed which, after filtration and drying, yielded 15.13 g of the product (86% yield).

δ _Η (400 MHz, CDCl ₃ ) 1.56 (6H, s), 3.35 (3H, s), 3.37 (3H, s), 3.7-3.71 (4H, m), 4 13.4.19 (4H, m), 7.0 (1H, m), 7.13-7.17 (2H, m), 7.3 (1H, m), 7.6 (2H, m) ), 8.55 (1H, s); m / e 452 (M + H) < ^{+ &gt};.

Example 7

Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine monohydrochloride

4- [3 - [[6,7-Bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] 2-methyl-3-butin-2-ol monohydrochloride (32.34 g, 66) prepared as described above. , 3 mmol), water (300 mL) and 1-butanol (600 mL) were stirred together at room temperature to form a mixture. The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide and the mixture was divided into two layers. The organic layer was separated from the aqueous layer and concentrated under atmospheric pressure by removing water from the 1-butanol solution in azeotropic manner. The final volume of the 1-butanol solution was approximately 300 ml. Anhydrous solid sodium hydroxide (0.13 g, 3.3 mmol) was added to the azeotropically dried 1-butanol solution and the resulting mixture was heated to reflux at 115-120 ° C and held at this temperature for 24 hours. 1-Butanol (150 mL) was removed by distillation and the concentrated reaction mixture was cooled to 15-25 ° C. Concentrated hydrochloric acid (6.1 ml) and 1-butanol (60 ml) were added to the cooled concentrate and the mixture was granulated overnight at 20-25 ° C and crystallized at this temperature. The crystals of the title product were isolated by filtration and de-evaporated in vacuo at 45-50 ° C. In this way, 21.0 g of the title product was obtained (73.7% yield) with 96.5% purity (HPLC).

Example 8

Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine, methanesulfonic acid salt

4- [3 - [[6,7-Bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] -2-methyl-3-butin-2-ol monohydrochloride prepared as described above (32.34 g, 66.3 mmol) ), water (300 mL) and 1-butanol (600 mL) were stirred together at room temperature to form a mixture. The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide and the mixture was divided into two layers. The organic layer was separated from the aqueous layer and concentrated under atmospheric pressure by removing water from the 1-butanol solution in azeotropic manner. The final volume of the 1-butanol solution was approximately 300 ml. Anhydrous solid sodium hydroxide (0.13 g, 3.3 mmol) was added to an azeotropically dried 1-butanol solution and the resulting mixture was heated to reflux at 115-120 ° C and held at this temperature for 24 hours. The reaction mixture was cooled to 15-25 ° C, methanesulfonic acid (4.6 mL) was added to the cooled concentrate, and the mixture was granulated overnight at 20-25 ° C and crystallized at this temperature. The crystals of the title product were isolated by filtration, washed with 1-butanol (25 ml), and freed from 1-butanol by evaporation under vacuum at 45-50 ° C. This afforded 29.16 g of the title product (90% yield) with 96.7% purity (HPLC).

Example 9

Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine monohydrochloride

4- [3 - [[6,7-Bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] -2-methyl-3-butin-2-ol (20.0 g, 44.3) mmol), anhydrous solid sodium hydroxide (0.09 g, 2.2 mmol) and 2-butanol (400 mL) were combined and heated to reflux at 100-102 ° C for 36 hours. The reaction mixture was cooled to 15-25 ° C and concentrated hydrochloric acid (4.1 mL) was added to the cooled mixture. The resulting mixture was granulated overnight at 20-25 ° C and crystallized at this temperature. The title product crystals were collected by filtration, washed with 2-butanol (25 mL), dried under vacuum at 45-50 ° C and after removal of 2-butanol gave 17.7 g of product (93% yield) with 99.1% purity (HPLC ).

Example 10

Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine monohydrochloride

4- [3 - [[6,7-Bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] -2-methyl-3-butin-2-ol (20.0 g,

44.3 mmol), anhydrous solid sodium hydroxide (260 mg, 6.5 mmol) and 2-propanol (200 mL) were mixed, heated to 135-140 ° C in a pressure vessel and held at this temperature for 23 hours. The reaction mixture was cooled to 60-65 ° C and concentrated hydrochloric acid (4.8 mL) was added to the cooled mixture. The resulting mixture was granulated overnight at 20-25 ° C and crystallized at this temperature. The mixture was treated with water (10 ml) and stirred at 58-68 ° C for 21 hours, cooled to 15-20 ° C and granulated for 2 hours. The title product crystals were collected by filtration, washed with 2-propanol (2 x 30 mL), dried under vacuum at 45-50 ° C, and after removal of 2-propanol gave 17.6 g of product (92% yield).

Example 11

Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine monohydrochloride

4- [3 - [[6,7-Bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] -2-methyl-3-butin-2-ol (5.0 g, 11 mmol) prepared above , anhydrous solid sodium hydroxide (44 mg, 11 mmol) and 2-methoxyethanol (50 mL) were combined and refluxed for 47 hours. The reaction mixture was cooled to 20-25 ° C and concentrated hydrochloric acid (1.1 mL) was added to the cooled mixture. The resulting mixture was granulated for 1 hour at 20-25 ° C and crystallized at this temperature. The crystals of the title product were isolated by filtration, washed with 2-methoxyethanol (10 mL), dried under vacuum at 45-50 ° C and after removal of 2-methoxyethanol gave 3.73 g of the product (78% yield).

Example 12

Preparation of N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine, methanesulfonic acid salt

4- [3 - [[6,7-Bis (2-methoxyethoxy) -4-quinazolinyl] amino] phenyl] -2-methyl-3-butin-2-ol (20.0 g, 44.3) mmol), anhydrous solid sodium hydroxide (0.09 g, 2.2 mmol) and 2-butanol (400 mL) were combined and heated to reflux at 100-102 ° C for 36 hours. The reaction mixture was cooled to 15-25 ° C and methanesulfonic acid (5.1 g, 53.2 mmol) was added to the cooled mixture. The resulting mixture was granulated overnight at 20-25 ° C and at this temperature

Crystallization also occurred at temperature. The title product crystals were isolated by filtration, washed with 2-butanol (25 mL), dried under vacuum at 45-50 ° C and after removal of 2-butanol gave 19.45 g of product (90% yield) with 98.5% purity (HPLC ).

Example 13

Preparation of N- (3-ethylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine

4-Chloro-6,7-bis (2-methoxyethoxy) quinazoline (50 g, 160 mmol),

3-ethylaniline (21.34 g, 176 mmol) and 2-propanol (500 mL) were heated to 78-82 ° C and held at this temperature for 16 hours. The mixture was cooled to 5-10 ° C and stirred for 1 hour. The solid was collected by filtration and treated with water (200 mL) and ethyl acetate (500 mL). The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide solution and the mixture was partitioned. The organic layer was separated and washed with water (200 mL), brine (200 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was allowed to solidify and dried under vacuum at 20-25 ° C to give the title product (57.2 g, 90% yield) as a white solid, mp 72-74 ° C.

δ _Η (300 MHz; CDCl ₃ ) 1.16 (3H, t, J = 7.6), 2.58 (2H, q, J =

7.6), 3.32 (3H, s), 3.34 (3H, s), 2.01-2.47 (2H, m), 2.082.54 (2H, m), 4.07-4 12 (4H, m), 6.91 (1H, d, J = 7.6), 7.11 (1H, s), 7.21 (1H, t, J = 7.8), 7.35 (IH, s), 7.42 (IH, s),

7.48 (1H, d, J = 8.0), 8.13 (1H, bs), 8.58 (1H, s); Δ _c (75.5 MHz; CDCl ₃ ) 15.4, 28.8, 59.1, 68.2, 68.9, 70.4, 70.8, 103.0,

108.3, 109.3, 119.7, 121.7, 123.9, 128.8, 138.6, 145.1,

147.0, 148.6, 153.6, 154.4, 156.9;

Ν max ^{(KBr) cm -1 3136 (s)} ' ¹⁶²⁴ ' ^{1575 (s)} ' ^{1535 (s)} ' ¹⁴⁸⁷ (s); m / z 398 (M + H) ^< ^{+ &gt};;

elemental analysis: calculated for ^C 22 ^H 27 ^N 3 ° · ^{0 '25} H 2 O: C,

65.73%; H, 6.90%; N, 10.45%; found: C, 65.64%; H, 6.96%; N, 10.32%.

Example 14

Preparation of N- (3-ethylphenyl) -6- (2-methoxyethoxy) -7-benzyloxy-4-quinazolinamine

N- (3-ethylphenyl) -6,7bis (2-methoxyethoxy) -4-quinazolinamine (4.0 g, 10 mmol), solid anhydrous sodium hydroxide (104 mg, 2.6 mmol) and benzyl alcohol (as described above) were prepared as described above. 20 ml) was heated to 150-152 ° C and maintained at this temperature for 23 hours. The reaction mixture was allowed to cool to room temperature and purified by silica gel column chromatography using a gradient eluent of ethyl acetate and hexane to give a white solid which, after drying under vacuum at 45-50 ° C, gave the title product (2.52 g, 58% yield), m.p. 156-157 ° C.

δ _Η (300 MHz; CDCl ₃ ) 1.17 (3H, t, J = 7.6), 2.58 (2H, q, J =

7.6), 3.33 (3H, s), 3.65-3.68 (2H, m), 4.07-4.11 (2H, m),

5.11 (2H, s), 6.83 (1H, d, J = 7.7), 7.18-7.29 (5H, m), 7.35-7.42 (4H, m), 7.50 (1H, d, J = 8.0), 8.20 (1H, bs),

8.61 (1 H, s); Δ _c (75.5 MHz; CDCl ₃ ) 14.2, 15.4, 28.8, 59.2,

69.2, 70.7, 70.8, 103.2, 109.1, 109.4, 119.7, 121.7, 124.0,

127.3, 128.1, 128.5, 128.8, 135.8, 138.6, 145.1, 147.0,

148.9, 153.7, 154.2, 156.9;

characterized d max ^RBR) θ® ^"1 1625, 1611, 1576; m / z 430 (M + H) ^< ^{+ &gt};; Elemental analysis: calculated for C ₂₆ H ₂₇ N ₃ O ₃ : C, 72.70%;

H, 6.34%; N, 9.78%; found: C, 71.42%; H, 6.50%; N, 9.48%

Example 15

Preparation of N- (3-ethylphenyl) -6- (2-methoxyethoxy) -7-butyloxy-4-quinazolinamine

Prepared above N- (3-ethylphenyl) -6,7-bis (2-methoxyethoxy) 4-quinazolinamine (4.0 g, 10 mmol), solid anhydrous sodium hydroxide (94 mg, 2.36 mmol) and 1-butanol (20 ml) was refluxed for 12 days. The reaction mixture was allowed to cool to room temperature, purified by silica gel column chromatography using a gradient eluent of ethyl acetate and hexane to give a white solid which, after drying under vacuum at 45-50 ° C, afforded the title product (2.57 g, 65% yield), m.p. 90-92 ° C.

δ _Η (300 MHz; CDCl ₃ ) 0.93 (3H, t, J = 7.4), 1.19 (3H, t, J =

7.6), 1.45 (2H, sextet, J = 7.5), 1.79 (2H, pentet, J = 6.9), 2.61 (2H, q, J = 7.6), 3.39 (3H, s), 3.70-3.74 (2H, m), 4.00 (2H, t, J = 6.6), 4.12-4.15 (2H, m), 6.94 (1 H, d, J = 7.7),

7.15 (1H, s), 7.24 (1H, t, J = 7.8), 7.34 (1H, s), 7.44 (1H, s), 7.51 (1H, d, J = 8.0), 7.95 (1H, bs), 8.60 (1H, s); Δ _C (75.5 MHz? CDCl ₃ ) 13.8, 15.4, 19.2, 28.8, 30.8, 59.3, 68.7,

69.3, 70.9, 103.2, 108.2, 108.9, 119.6, 121.6, 124.0, 128.9, 138.6, 145.2, 147.2, 148, 8, 153.6, 154.9, 156.8;

IN? _max (KBr) cm ^-1 1618, 1576, 1519; m / z 396 (M + H) ^< ^{+ &gt};;

elementary analysis; Calcd for C23 ^H 29 ^N 3 ^{O 3:} C, 69.85%;

H, 7.39%; N, 10.63%; found: C, 70.0%; H, 7.56%; N,

10.66%.

Example 16

Preparation of N- (4-methoxyphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine

4-Chloro-6,7-bis (2-methoxyethoxy) quinazoline (25 g, 79.9 mmol), 4-anisidine (9.8 g, 79.9 mmol) and 2-propanol (250 mL) were warmed to temperature 78-82 ° C and held at this temperature for 16 hours. The mixture was cooled to 5-10 ° C and stirred for 1 hour. The solid was collected by filtration and rinsed with 2-propanol (25 mL). The isolated solid was recrystallized from ethanol-water and after drying overnight in a vacuum oven at 40-45 ° C, it was mixed with water (100 mL) and ethyl acetate (250 mL). The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide and the mixture was divided into two layers. The organic layer was separated and washed with water (200 mL), brine (200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid which was dried under vacuum at 40-45 ° C to give the desired product (20 mL). (86 g, 65% yield) mp 186-187 ° C.

δ _Η (300 MHz; CDCl ₃ ) 3.31 (3H, s), 3.35 (3H, s), 3.62-3.65 (2H, m), 3.70-3.72 (2H, m), 3.74 (3H, s), 4.04-4.11 (4H, m), 6.83 (2H, d, J = 9.0), 7.09 (1H, s), 7 33 (1H, s), 7.46 (2H, d, J = 9.0), 8.12 (1H, bs), 1H, s); 5 _C (75.5 MHz, CDC1 ₃₎

55.4, 59.2, 68.2, 69.0, 70.4, 70.8, 103.1, 108.3, 109.1,

114.2, 124.7, 131.4, 146.8, 148.6, 153.7, 154.3, 156.7,

157.3;

characterized max ^{(KBr) cm -1} 1 ^{9 16} »1590, 1582, 1511; m / z 400 (M + H) ^< ^{+ &gt};; Elemental analysis: calculated for C ₂₁ H ₂₅ N ₃ O ₃ : C, 63.42%; H, 6.31%; N, 10.52%; found: C, 63.30%; H, 6.37%; N, 10.47%.

Example 17

Preparation of N- (4-methoxyphenyl) -6- (2-methoxyethoxy) -7-benzyloxy-4-quinazolinamine

N- (4-methoxyphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinamine (2.0 g, 4.6 mmol), solid anhydrous sodium hydroxide (104 mg, 2.6 mmol) and benzyl alcohol prepared above (20 mL) was heated to 145-150 ° C and held at this temperature for 18 hours. The reaction mixture was allowed to cool to room temperature, purified by silica gel column chromatography using a gradient eluent of ethyl acetate and hexane to give a white solid which, after drying under vacuum at 45-50 ° C, afforded the title product (0.915 g, 42%). 208 DEG-209 DEG.

Δ _H (300 MHz; CDCl ₃ ) 3.34 (3H, s), 3.91 (2H, t, J = 4.2), 3.74 (3H, s), 4.10 (2H, bs) 5.13 (2H, s), 6.83 (2H, d, J = 8.9), 7.20-7.30 (5H, m), 7.36-7.38 (3H, m) 7.47 (2H, d, J = 8.9), 8.10 (1H, bs), 8.54 (1H, s); & _C (75.5 MHz, CDC1 ₃₎ 55.5,

59.3, 69.2, 70.7, 70.9, 103.3, 109.0, 109.1, 114.2, 124.6,

127.3, 128.1, 128.5, 131.3, 135.8, 146.8, 148.8, 153.7,

154.2, 154.2, 156.8, 157.2;

7max ^(KBr > ^{cm -1 1619} · ¹⁵⁸⁰ → 1511; ^m / ^{z 432} (M + H) ⁺ ;

Elemental analysis: calculated for ^C 25 ^H 25 ^N 3 ^O 4 ^{: C 69} H ⁵⁹ , 5.84%; N, 9.74%; found: C, 69.48%; H, 5.85%; N,

9.68%.

Example 18

Preparation of N-phenyl-N-methyl-6,7-bis (2-methoxyethoxy) -4-quinazolinamine

4-Chloro-6,7-bis (2-methoxyethoxy) quinazoline (10 g, 31.97 mmol), N-methylaniline (3.5 mL, 31.97 mmol) and acetonitrile (100 mL) were warmed to 78 to 82 ° C and maintained at this temperature for 24 hours. The mixture was cooled to 5-10 ° C and stirred for 0.5 hours. The solid was collected by filtration and dried in a vacuum oven at 50-55C for 5 hours. The isolated solid was mixed with water (50 mL) and ethyl acetate (200 mL). The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide and the mixture was divided into two layers. The organic layer was separated, washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid which was dried under vacuum at 50-55 ° C to give the desired product (8). 55 g (70% yield), m.p. 109-111 ° C.

δ _Η (300 MHz; CDCl ₃ ) 3.33 (3H, s), 3.39 (3H, s), 3.42-3.45 (2H, rn), 3.48-3.51 (2H, m), 3.58 (3H, s), 3.74-3.78 (2H, m), 4.16-4.20 (2H, m), 6.33 (1H, s), 7.11 -7.20 (4H, m), 7.83 (2H, t, J = 7.8), 8.68 (1H, s); Δ _c (75.5 MHz; CDCl ₃ ) 42.0, 59.2, 59.3, 67.6, 68.2, 70.3, 70.4, 106.5, 107.9, 110.9 , 125.8, 126.0, 129.9, 147.0, 148.4, 148.7, 153.0, 153.4,

160, 4

Ν max ( ^KBr ) ^1615/1571 , 1497; m / z 384 (M + H) ^< ^{+ &gt};;

Elemental Analysis calculated for ^C 21 ^H 25 ^N 3 ° ^{4: C "65"} * ⁷⁸ "H, 6.57%; N, 10.96%; found: C, 65.85%; H, 6.52%; N, 11.01%.

Example 19

Preparation of N-phenyl-N-methyl-6- (2-methoxyethoxy) -7-butyloxy-4-quinazolinamine

N-Methyl-N-phenyl-6,7bis (2-methoxyethoxy) -4-quinazolinamine (1.0 g, 2.61 mmol) prepared as described above, solid anhydrous sodium hydroxide (97.5 mg, 2.43 mmol) ) and 1-butanol (10 ml) were refluxed for 24 hours. The reaction mixture was allowed to cool to room temperature and purified by silica gel column chromatography using a gradient eluent of ethyl acetate and hexane to give a white solid which after drying in vacuo at 45-50 ° C gave the title product (517 mg, 52% yield). mp 62-63 ° C.

δ _Η (300 MHz; CDCl ₃ ) 0.93 (3H, t, J = 7.4), 1.45 (2H, sextet,

J = 7.4), 1.80 (2H, pentet, J = 6.7), 3.35 (3H, s), 3.44-3.52 (4H, m), 3.59 (3H, s); s), 4.05 (2H, t, J = 6.7), 6.34 (1H, s), 7.12-7.21 (4H, m), 7.34 (2H, t, J = 7.7), 8.69 (1H, s);

(75.5 MHz; CDCl ₃ ) 13.8, 19.2, 30.7, 42.0, 59.2, 67.8, 68.6,

70.4, 106.5, 107.7, 110.6, 125.8, 125.9, 129.9, 147.0, 148.6, 153.0, 153.8, 160.4;

Ϋ max ^<KBr) C ^"1 1616, 1572, 1543; m / z 382 (M + H) ^&lt; ^{+ &gt};;

Elemental Analysis calculated for ^C 22 ^H 27 ^N 3 ° ^3: C, 69.27%;

H, 7.14%; N, 11.02%; found: C, 69.39%; H, 7.38%; N,

10.86%.

Claims (17)

7 (/ - 2 & V-V or a pharmaceutically acceptable salt or solvate thereof) wherein: Ί o R and R * are each independently selected from C 1 -C 10 alkyl and C 1 -C 10 alkoxy, wherein both alkyl and alkoxy are optionally substituted with a maximum of 2 substituents independently selected from hydroxy and C 1 -C 6 alkoxy alkyl; R ¹⁵ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or - (CH ₂ ) g (C ₆ -C ₁₀ aryl) wherein q represents an integer from 0 to 4; characterized in that it comprises treating a compound of formula 2 wherein R ¹⁵ , R ¹ and R ² are as defined above and G is a blocking group selected from -C (OH) R ³ R ⁴ and -SiR ³ R ⁴ R ⁵ ; R ³ , R ⁴ and r ⁵ are each independently C 1 -C 6 alkyl; either (a) an alkali metal or an alkali metal hydroxide in a solvent containing a C 1 -C 10 alkyl group substituted with a hydroxy group when G is -C (OH) R ³ R ⁴ , or (b) a tetra (C 1 -C 6 alkyl) ammonium fluoride compound in an aprotic solvent when G is -SiR ³ R ⁴ R ⁵ . The process according to claim 1, wherein G is -C (OH) R ³ R ⁴ , the solvent is a secondary alcohol and the alkali metal or alkali metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. 3. The process of claim 2 wherein the solvent is 2-butanol or isopropanol or a mixture of the two and the alkali metal or alkali metal hydroxide is sodium hydroxide. A process according to claim 1 wherein G is -SiR ³ R ^{4, the} tetra (C 1 -C 6 alkyl) ammonium fluoride compound is tetra (n-butyl) ammonium fluoride and the aprotic solvent is selected from tetrahydrofuran, diethyl ether, dimethoxyethane, toluene. , dichloromethane, chloroform and a mixture of two or more of these solvents. A process according to claim 1, wherein both R ¹ and R ² are 2-methoxyethoxy and R ¹⁵ is hydrogen. 6. A process according to claim 1, wherein the compound of formula 2 is prepared by treating a compound of formula 3. wherein R ¹ and R ² are as defined in claim 1, a compound of formula 4 wherein R ⁵ and G are as defined in claim 1. The method of claim 6, wherein the compound of Formula 3 is treated with a compound of Formula 4 in an organic solvent selected from dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, and a mixture of two or more of these solvents. A process according to claim 7, wherein the solvent is acetonitrile, both R ¹ and R ² are 2-methoxyethoxy and R ¹⁵ is hydrogen. 9. The process of claim 6 wherein the compound of formula 3 is prepared by treating the compound of formula 5 with thionyl chloride in anhydrous dichloromethane. The process of claim 9, wherein both R ¹ and R ² are 2-methoxyethoxy. A process for the preparation of a compound of formula 6 or 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ represents an alkyl group having 1 to 10 carbon atoms or - (CH ₂ ) _m O (CH ₂ ) _n CH ₃ ; R ⁷ represents an alkyl group having 1 to 10 carbon atoms or an alkylaryl group having 1 to 6 carbon atoms in the alkyl radical and 6 to 10 carbon atoms in the aryl radical, both of which are optionally substituted with 1 to 3 substituents independently selected from halo, nitro trifluoromethyl, trifluoromethoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy and C 6 -C 10 arylsulfonyl; each m is independently an integer from 1 to 6 and n is an integer from 0 to 3; R ( ¹⁵⁾ is hydrogen, (C1-C10) alkyl or - (CH2 ₎ C1-C6-Caryl) wherein q is an integer from 0 to 4; characterized in that it comprises treating a compound of formula 8 wherein R ⁶ and R ¹⁵ are as defined above; G ¹ is -C (OH) R ³ R ⁴ and R ³ and R ⁴ each independently represent an alkyl group having 1 to 6 carbon atoms; a primary or secondary alcohol R ⁷ -OH, wherein R ⁷ represents an alkyl group having 1 to 10 carbon atoms or an arylalkyl group having 6 to 10 carbon atoms in the aryl radical and 1 to 6 carbon atoms in the alkyl radical, and these R ⁷ groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, alkylsulfonyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryloxy of 6 to 10 carbon atoms and (C 6 -C 10) arylsulfonyl; in the presence of an alkali metal or an alkali metal hydroxide. The process of claim 11, wherein the alkali metal or alkali metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. A process according to claim 12, wherein the alkali metal or alkali metal hydroxide is sodium hydroxide, R ⁶ is 2-methoxyethoxy, R ¹⁵ is a hydrogen atom, and the alcohol of formula R ⁷ -OH is a secondary alcohol. zna41 A process for the preparation of a compound of formula 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is C 1 -C 10 alkyl or - (CH ₂ ) _m O (CH ₂ ) _n CH ₃ ; • 7 R is C 1 -C 10 alkyl or C 6 -C 10 arylalkyl of aryl and C 1 -C 6 alkyl and these R ⁷ groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, alkylsulfonyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryloxy of 6 to 10 carbon atoms and arylsulfonyl of 6 to 10 carbon atoms; each m independently represents an integer from 1 to 6 and n represents an integer from 0 to 3; R ⁸ , R ⁹ and R ¹⁰ are each independently selected from hydrogen, C 1 -C 10 alkyl, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -or ¹¹ , -cir ¹¹ , -c (o) or ^{i: l} , -nr ¹² c (o) or ¹⁴ , -oc (o) r ^{i: l} , nr ¹² so2r ¹⁴ , -so2nr ^{i: l} r ¹² , -nr ¹² c (o) r ^{i: 1} , -c (o) nr ^{1: l} r ¹² , -ΝΚ ¹³ Έ ¹² , -S (O) j (CH ₂ ) q (C ₆ -C ₁₀ aryl), -S (O) j (C 1 -C 6 alkyl) wherein j is an integer from 0 to 2, - (CH ₂ ) g ( (C ₆ -C ₁₀ aryl), -O (CH ₂ ) _q (C ₆ -C ₁₀ aryl), -NR ¹² (CH ₂ ) _q (C ₈ -C ₁₀ aryl), and - (CH 2) q (4 to 10-membered heterockylus) ) wherein q is an integer from 0 to 4; said alkyl group optionally having 1 or 2 hetero groups selected from oxygen, -S (O) j - in which j is an integer from 0 to 2, and -N (R ¹² ) - provided that two oxygen atoms, two the sulfur atoms or the oxygen atom and the sulfur atom are not directly attached thereto; the aryl and heterockyl groups are optionally fused to an aryl group having 6 to 10 carbon atoms, a saturated cyclic group having 5 to 8 carbon atoms, or a 4- to 10-membered heterocyclic group; and the alkyl, aryl and heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR ¹² SO 2 R ¹⁴ , -SO ² NR ¹³ -R ¹² , -C ¹ R ¹¹ C ¹¹ -C ¹¹ O-R ¹¹ , -NR ¹² (O) R ¹¹ , -C (O) NR ¹¹ R ¹² , -NR ^{11 :} R ¹² , -OR ¹¹ , (C 1 -C 10) -alkyl, - (CH 2) _q (C 8 -C ₁₀ aryl) and - (CH ₂ ) _q (4- to 10-membered heterocycle) wherein q is an integer from 0 to 4; each R ¹¹ is independently selected from hydrogen, C 1 -C 10 alkyl, - (CH ₂ ) _q (C 8 -C ₁₀ aryl), and - (CH ₂ ) g (4- to 10-membered heterocycle); wherein q is an integer from 0 to 4; wherein the alkyl group optionally comprises 1 or 2 hetero groups selected from oxygen, -S (O) j - in which j is an integer from 0 to 2, and -N (R ¹² ) - provided that two oxygen atoms, two the sulfur atoms or the oxygen atom and the sulfur atom are not directly attached thereto; the aryl and heterocyclic groups R ¹¹ are optionally fused to an aryl group having 6 to 10 carbon atoms, a saturated cyclic group having 5 to 8 carbon atoms, or a 4- to 10-membered heterocyclic group; and the above R ¹¹ substituents, with the exception of hydrogen, are optionally substituted with 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R ¹² , -C (O) ) OR ^12, -OC (O) R ^12, -NR ¹² C (O) R ^13, -C (O) NR ¹² R ^13, -NR ¹² R ^13, hydroxy, alkyl of 1 to 6 carbon atoms and alkoxy C 1 -C 6; each R ^{XZ 1} and R ^XJ is independently hydrogen or C 1 -C 6 alkyl; R ^3-4 is selected from the substituents provided in the definition of R ¹¹ , except that R ^{14 is} not hydrogen; R ¹⁵ is hydrogen, C 1 -C 10 alkyl, or - (CH 2) q (C 8 -C ₁₀ aryl) wherein q is an integer from 0 to 4; characterized in that it comprises treating a compound of formula 10 wherein R ¹⁵ , R ⁶ , R ⁸ , R ⁹ and R ^{10 are} as defined above; a primary or secondary alcohol of the formula R ⁷ -OH, wherein R ⁷ is an alkyl group having 1 to 10 carbon atoms or an arylalkyl group having 6 to 10 carbon atoms in the aryl radical and 1 to 6 carbon atoms in the alkyl radical, and these R ⁷ groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, alkylsulfonyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryloxy groups (C 6 -C 10) atoms and (C 6 -C 10) arylsulfonyl groups; in the presence of an alkali metal or an alkali metal hydroxide. The process according to claim 14, wherein the alkali metal or alkali metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. 16. The method according to claim 15, characterized in that said alkali metal hydroxide or alkali metal hydroxide and an alcohol of formula R ⁷ -OH is a primary alcohol. A compound of formula 2 wherein R ¹ and R ^{2 are} each independently selected from C 1 -C 10 alkyl and C 1 -C 10 alkoxy, both alkyl and alkoxy being optionally substituted with a maximum of 2 substituents independently selected from C 1 -C 10 alkyl; hydroxy and (C 1 -C 6) alkoxy; G is a blocking group selected from -C (OH) R ³ R ⁴ and -SiR ³ R ⁴ R ⁵ ; R ³ , R ⁴ and R ⁵ each independently represent an alkyl group having 1 to 6 carbon atoms; and R ¹⁵ is hydrogen, C 1 -C 10 alkyl or - (CH ₂ ) q (C 8 -C ₁₀ aryl) wherein q is an integer from 0 to 4.